Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint

  • Cell Rep. 2024 May 28;43(5):114209. doi: 10.1016/j.celrep.2024.114209.
Rachel Mardjuki  1 ,  Songnan Wang  2 ,  Jacqueline Carozza  3 ,  Bahar Zirak  4 ,  Vishvak Subramanyam  4 ,  Gita Abhiraman  5 ,  Xuchao Lyu  6 ,  Hani Goodarzi  4 ,  Lingyin Li  7
Affiliations
  • 1. Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA; Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
  • 2. Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA.
  • 3. Arc Institute, Palo Alto, CA 94304, USA.
  • 4. Arc Institute, Palo Alto, CA 94304, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biophysics & Biochemistry, University of California, San Francisco, San Francisco, CA 94143, USA; Baker Computational Health Science Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 5. Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
  • 6. ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • 7. Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; ChEM-H Institute, Stanford University, Stanford, CA 94305, USA; Arc Institute, Palo Alto, CA 94304, USA. Electronic address: [email protected].
PMID: 38749434 DOI: 10.1016/j.celrep.2024.114209
Abstract

2'3'-Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) is a second messenger synthesized upon detection of cytosolic double-stranded DNA (dsDNA) and passed between cells to facilitate downstream immune signaling. Ectonucleotide pyrophosphatase phosphodiesterase I (ENPP1), an extracellular enzyme, was the only metazoan hydrolase known to regulate cGAMP levels to dampen anti-cancer immunity. Here, we uncover ENPP3 as the second and likely the only Other metazoan cGAMP hydrolase under homeostatic conditions. ENPP3 has a tissue expression pattern distinct from ENPP1's and accounts for all cGAMP hydrolysis activity in ENPP1-deficient mice. Importantly, we also show that, as with ENPP1, selectively abolishing ENPP3's cGAMP hydrolysis activity results in diminished Cancer growth and metastasis of certain tumor types in a stimulator of interferon genes (STING)-dependent manner. Both ENPP1 and ENPP3 are extracellular Enzymes, suggesting the dominant role that extracellular cGAMP must play as a mediator of cell-cell innate immune communication. Our work demonstrates that ENPP1 and ENPP3 non-redundantly dampen extracellular cGAMP-STING signaling, pointing to ENPP3 as a target for Cancer Immunotherapy.

Keywords
CP: Immunology; ENPP1; ENPP3; PD-1; STING; breast cancer; cGAMP; clinical trial; hydrolase; immune checkpoint; melanoma.